Renal handling of uric acid in man and other mammals is thought to result from complex mechanisms involving glomerular filtration, tubular reabsorption, and tubular secretion. The relative importance of transepithelial urate movement in each direction varies somewhat but appears to be present in all mammalian species. Attempts to localize the anatomic sites of predominant uric acid reabsorption and secretion along the mammalian nephron by micropuncture or "stop flow" clearance techniques have yielded conflicting results. In this project we will attempt to precisely define the nephron loci of tubular reabsorptive and secretory dominance for uric acid in a mammalian species by using the technique for perfusing isolated segments of the rabbit nephron in vitro. Moreover, by determining the tissue to bathing medium gradient for isotopic uric acid of perfused versus non-perfused tubules, we should be able to develop a three compartment model (luminal, cellular, and peritubular fluid) of uric acid transport for each segment of the rabbit nephron. In this manner we will define the mechanism by which uric acid is transported across the renal tubular epithelium (i.e., "active" uptake being located either at the luminal or peritubular membrane of the renal tubular cell). With the basic mechanism of uric acid transport so defined, we should then be able to evaluate directly the effects of various pharmacologic agents on each limb (secretory vs. reabsorptive component) of transtubular uric acid transport in vitro and compare these results to their overall uricosuric or anti-uricosuric effects in vivo. A correlation between in vitro and in vivo renal uric acid transport in the rabbit will be made by obtaining clearance data in the rabbits prior to their sacrifice and the use of their tubules for in vitro microperfusion studies. This study should provide a unequivocal definition of renal tubular uric acid transort by direct examination along the entire length of the rabbit nephron.